Rapid and widespread emergence of antibiotics-resistant pathogens creates an urgent need for concerted approaches towards novel antiinfectives. The long-term objective of this proposal is the development of novel potent antibacterials that target the ribosomal RNA (rRNA) of antibiotics-resistant bacteria. Specifically, a lead series of small molecules that recognize the ribosomal decoding-site RNA (A-site) will be developed to select an antibacterial drug candidate by iterative rounds of synthesis and testing for target binding, inhibition of protein synthesis and bacterial growth. The ribosomal A-site constitutes a prime target for antibiotics, validated by the naturally occurring aminoglycosides and a novel series of chemically unrelated antibacterials that we have discovered recently. Rational structure-based design along with multi-dimensional drug optimization, using testing data from a range of biochemical and biological assays, will allow us to develop a novel class of antibiotics that are not susceptible to known bacterial resistance mechanisms. These novel antibacterial A-site ligands will constitute the first class of antibiotics that has been developed by a rational approach of drug discovery specifically directed at an RNA component of the bacterial ribosome. [unreadable] [unreadable]